There is accumulating evidence that the chronic-low grade inflammation associated with obesity plays an important role in the development of metabolic disease. Although a number of molecular pathways connecting inflammation and metabolism have been discovered, numerous gaps remain in our understanding of how inflammatory signals disrupt normal glucose and lipid homeostasis, particularly concerning the role of different cytokines. This is especially true of the classic inflammatory cytokine, Il-6. Although elevated Il-6 levels are a risk factor for the development of metabolic disease, numerous beneficial effects of the cytokine on glucose metabolism have been observed. Il-6 appears to be is a key player in a subcutaneous adipose tissue:hepatic axis, whereby Il-6 secreted from subcutaneous adipose tissue suppresses hepatic gluconeogenesis via the phosphorylation and activation of Stat3. The noncanonical I?B kinases Ikk-? and Tbk1, which are induced downstream of the inflammatory mediator NF-?B, suppress this axis in the obese state. Inhibition of Ikk-?/Tbk1 by the drug amlexanox restores the balance of this axis, providing an ideal system for investigating the in vivo effects of Il-6 signaling in the context of obesity. Using this established system, Il-6 signaling and its effects on metabolic disease will be examined. The first aim will focus on the hepatic effects of Il-6 and their dependence on hepatic Stat3 activation. The second aim will investigate the extra hepatic effects of Il-6 signaling on glucose metabolism, looking into the regulation of glucose handling in peripheral tissues and the specific role of Glp-1 in the pancreas. The third aim will focus on Il-6 signaling within the adipoe tissue, from adipocytes to immune cells. The applicant's long-term career goal is to make a significant contribution to the understanding of the pathology of obesity and the development of metabolic disease. This career development award will enable the applicant to develop the skills required to become an independent investigator, leading a basic research laboratory at an academic institution in a tenure track faculty position, where the applicant will have the best chance of achieving her long-term goal. These skills will be developed at the University of Michigan, an excellent environment in which to perform health sciences related research, with many available resources including career development workshops. The Life Sciences Institute provides a fantastic collaborative environment in which to perform basic research with translational potential. Collaborations between faculty and physicians provide opportunities for the translation of basic research into the clinical setting. The applicant will utilize the resourcs available at the University of Michigan, as well as guidance and support of the Mentoring and Advisory Committees, to complete the proposed research, and develop as an independent investigator.